Mechanism of action of corticosteroids in multiple sclerosis

Ricin is a potent cytotoxic protein derived from the higher plant Ricinus communis that inactivates eukaryotic ribosomes. In this paper we have studied the mechanism of action of ricin A-chain on rat liver ribosomes in vitro. Our findings indicate that the toxin inactivates the ribosomes by modifying both or either of two nucleoside residues, G4323 and A4324, in 28 S rRNA. These nucleotides are located close to the alpha-sarcin cleavage site and become resistant to all ribonucleases tested. The examination of the lability of phosphodiester bonds of these nucleotides to both mild alkaline digestion and aniline treatment at acidic pH suggests that the base of A4324 is removed by the toxin. This unique activity of ricin A-chain was also observed when naked 28 S rRNA is used as a substrate, indicating that the toxin directly acts on the RNA . Similar activity on 28 S rRNA is also exhibited by abrin and modeccin, ricin - related toxins, suggesting a general mechanistic pathway for ribosome inactivation by lectin toxins.

PHOENIX 1 evaluated 766 patients who received STELARA ® or placebo. The study design was identical to PHOENIX 2 through Week 28. Inclusion criteria were consistent with PHOENIX 2. At Week 40, 322 of the 511 patients initially randomized to STELARA ® who were PASI 75 responders at both Weeks 28 and 40 were rerandomized either to continue every-12-week dosing with STELARA ® (n=162) or to placebo (n=160). Patients rerandomized to STELARA ® at Week 40 were considered treatment failures if they discontinued STELARA ® due to unsatisfactory therapeutic effect, experienced an adverse event of worsening of psoriasis, or started nontopical, protocol-prohibited medications. 1,4 After Week 76, treatment was unblinded and treatment failure rules were relaxed to allow for use of concomitant topical medications, except for high-potency corticosteroids. The analyses from Week 76 through Week 244 included all patients rerandomized at Week 40 to continue every-12-week dosing with STELARA ® , except those who discontinued STELARA ® due to an adverse event or were lost to follow-up. 4,5

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